Heads of Laboratories
Our laboratory explores the development of an organism through structure/function analysis of regulatory complexes. We are particularly interested in understanding how genes are regulated during development and understanding the linkage between defective gene expression and human disease. A second focus area in our laboratory is the regulation of programmed cell death or apoptosis, which operates at the end of the useful life of a cell. Projects currently being studied cover five major research areas.
Transcriptional Regulation at the Promoter. We are exploring the fundamental basis for gene activation by analyzing the molecular consequences of activator engagement with RNA polymerase. Using the bacterial RNA polymerase sigma subunit, we have now established that activators impart promoter choice on the enzyme by repositioning the sigma factor DNA-binding surfaces within the holoenzyme to spatially constrain the presentation of these surfaces to DNA. Activators have also been demonstrated to unfold components of RNA polymerase to achieve this end. These studies represent the first molecular description of a gene activation event.
Transcriptional Regulation at a Distance. Eukaryotic gene regulation can be considered to be bipartite with the regulation of gene expression occurring at the promoter and at a distance by transcriptional enhancers. The enhancer complexes are assembled from several distinct DNA-binding proteins that form a higher-order structure of protein and DNA that directly influence the level of gene expression. The intriguing property of enhancer complexes is their relatively transient assembly and disassembly during development and their great distance from the promoter — often 4 to 50 kilobases away. Our laboratory has discovered that enhancer-binding proteins are not comprised of protein domains connected as "beads on a string." Instead, remarkable conformational dynamics are carried out by the enhancer-binding proteins to assemble a higher-order complex, which defines the specificity of gene expression. Through a combination of structure/function studies, normal and dysfunctional gene expression of both blood and bone are being investigated to understand the transcriptional basis of human leukemias and skeletal patterning defects. In this process, the molecular basis of transcriptional transactivation is to be defined.
Apoptosis. A relatively new area for the laboratory, there is great interest in understanding how cell death remains in check. Oddly, the cellular death signals are part of the normal life cycle of the cell. Our efforts are focused on understanding death initiation mechanisms. We have recently defined the general mechanism of death initiation at cell surface receptors, establishing the structural architecture and the functional pathway that re-programs a cell to die. The startling discovery that cell surface receptor pathways use a single, conserved biochemical mechanism for initiation of death suggests a pathway for the development of a new type of chemotherapy in which cell death pathways could be manipulated at will.
Development of Novel Antibiotics. As a correlate to our efforts at understanding eukaryotic gene activation, we are also pursuing the study of prokaryotic mechanisms of gene activation. The intent is to identify new targets for species-specific antibiotics that are transcription based. A novel protein has been studied that can be designed to target the housekeeping transcription system in any bacterium. This protein acts as a transcriptional co-activator for pathogens of bacteria. We aim to mimic this activity to kill the bacterial transcription apparatus in a eukaryotic host. Current efforts are aimed at targeting this new class of molecule against Mycobacterium tuberculosis.
NMR Spectroscopy. The principal tool of structural biology in the laboratory is NMR spectroscopy. We are developing new tools for the analysis of binary, ternary and quaternary protein and nucleoprotein complexes with an aim to extend practical NMR structural biology beyond 60 kilodaltons. We have further begun to explore practical routes to the study of hydrogen bonding in molecular recognition events within and between macromolecules.
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